| Consensus Statement | Quality of Evidence | Strength of Rec. | Study |
|---|---|---|---|
| Untreated symptomatic brain metastasis For patients with untreated active brain metastases who do not require immediate local therapy, tucatinib/trastuzumab/capecitabine combination is the preferred regimen (IA) for cases with brain tumor size < 2cm and systemic corticosteroid < 2mg/day dexamethasone equivalent, while T-DXd can be considered (IIA) beyond these preconditions if tucatinib has not been used. [Footnote] Evidence regarding the optimal sequencing of systemic therapy and local intervention remains limited | I-II | A | DB12 HER2CLIMB |
| Untreated asymptomatic biran metastasis For patient with untreated asymptomatic/inactive brain metastases, tucatinib/trastuzumab/capecitabine combination is preferred (IA) for cases with brain tumor size < 2cm and systemic corticosteroid < 2mg/day dexamethasone, while T-DXd plus pertuzumab can be considered for the patients with a DFI > 6 months after the prior chemotherapy (IB). | I | A | HER2CLIMB |
| Treated brain metastasis (upfront) For patients with stable brain metastases previously managed with local therapy, T-DXd, tucatinib/trastuzumab/capecitabine combination, and T-DXd plus pertuzumab are appropriate systemic treatment options. | I-II | A-B | DB01 DB03 DB12 HER2CLIMB |
| Treated brain metastasis (maintenance) For patients with stable brain metastases previously managed with local therapy, and achieved disease control after first‑line induction therapy (4-8 cycles of taxane/trastuzumab/pertuzumab combination) Tucatinib/trastuzumab/pertuzumab combination is a reasonable option for maintenance therapy Palbociclib/trastuzumab/pertuzumab/endocrine therapy combination is also a reasonable maintenance option for HR+ disease | II | B | HER2CLIMB05 PATINA |
| Treated brain metastasis (subsequent lines) For subsequent lines of systemic treatment, T-DXd, T-DM1, or capecitabine plus neratinib or lapatinib are recommended regimens for patients without prior exposure to these agents. For later line options, dual anti-HER2 and anti-HER2 plus chemotherapy can be considered, while Bevacizumab + Etoposide + Cisplatin (BEEP) can be considered after running out out anti-HER2 options. | I-II | A-B | EMILIA DB03 NALA BEEP |
| Leptomeningeal metastasis T-DXd, tucatinib/trastuzumab/capecitabine combination, BEEP and capecitabine plus neratinib are the reasonable systemic treatment options. | II | A-B | DEBBRAH ROSET-BM HER2CLIMB BEEP NALA |